Estrogen has beneficial effects on learning and memory and may also aid in the prevention of neurodegenerative diseases such as Alzheimer's disease (AD). Estrogen increases spine density and synaptogenesis of the CA1 pyramidal cells of the hippocampus, an area of the brain implicated in learning and memory and damaged in AD patients. Interestingly, this effect of estrogen on CA1 hippocampal cells shows a sex difference, such that females experience a greater increase in spine density and synaptogenesis than males. Thus far, these changes have only been documented morphologically using Golgi impregnation. The present set of proposed studies will greatly extend these findings by characterizing and quantifying the pre- and post-synaptic proteins and their mRNAs that contribute to these estrogen-induced morphological synaptic changes and sex differences. Furthermore, the mechanism by which estrogen affects spine density differently in males and females will be explored. Finally, additional experiments will provide novel information on how exposure to steroid hormones during prenatal development sexually differentiates the ability of estrogen to affect hippocampal synapses.